Experience with the once - daily calcium antagonist amlodipine on 24 - hour ambulatory blood pressure in hypertensive patients

170 Susalit and Sidabutar _{MedJ Univ Indon}

Experience

with

the

Once

- Daily

Calcium Antagonist

Amlodipine

on

24

-

Hour Ambulatory

Blood Pressure in Hypertensive Patients

E. Susalit, R.P. Sidabutar

Abstrak

Telah diteliti efekrivitos dan tolerabilitas penberian dosis tunggal antagonis kalsium antlodipin (5-10 nry) pada 20 penderita hipertensi _{ringandansedang. Untukmenilai efekanlodipin, selaindipakaisfig,nomanometer air raksajugadipergunakanalat pengukur} teka nan darah 24

ian

ambulatoar. Penguktran tekanan darah secara antbulatoar selatna 24 jam setelah pengobatan anlodipin selatna 8 ninggu, menperlihatlcan bahwa obat ini efektif menurunkan tekanan darah selana 24 jam, tanpa nerubah pola nonnal sirkadian.

Abstract

The antihypertensive efficacy and tolerability of once-daily calciunt antagonist antlodipine (5-10 ng) were studied in 20 patients with ttrild to moderate hypertensiotr. 24-hour anbulatory blood pressure nonitoring in conjunction with sphygnotnanonrctric

ur"^ur"-,nent were used to study the effects of anilodipine. 24-hour anbulatory blood pressure nonitoring nade after 8 weeks of treatrnent with amLodipine revealed that anilodipine effectively reduced blood pressure throughout the whole 24-h period without altering the nornnl circadian pattern.

Keyw ords : Anlodipine, hypertensi on, 24-hour anbulatory blood pressure

INTRODUCTION

Amlodipine,

a structural analog

of nifedipine,

the

first

of

the

l,4-dihydropyridine calcium

antagonists,

has

been

sho

of

hyper-tension.

I

shown in

Fig.t.2A

nelimina-tion half-life

of 35

h following

a single

oral

dose and

to

be

readily

absorbed

following oral

administration,

with

peak plasma levels

being

achieved 6-12

h

posf

dose.''* The pharmacokinetic

profile

of

amlodipine

allows once

daily administration,

which has

been

shown

to

reduce

blood

pressure

(BP)

measured

24 h

postdose.s The effective àntihypertensive dose appears to be 5

or

10 mg once

daily, with

simple

one-step dose

adjustment

required

to meet

individual patient's

re-qurrements."

The

purpose

of

this study was

to evaluate

the

antihypertensive efficacy

and

tolerability

of once-daily

amlodipine during normal

daily

activity using

24-h

ambulatory BP

monitoring

and

periodic

clinic

Bp

[image:1.595.311.556.346.652.2]

measurements.

Figure 1. The sffucture ofanùodipine

MATERIALS

AND

METIIODS

Patient

selection

Men

and women (not

of child

bearing

potential)

aged

between

2l

and 65 years,

who

had

mild to

moderate

hypertension

with

supine and standing diastolic Bp

H3COOC

Hsc

ct

cooc2Hs

cH2ocH2cH2NH2

N

I

H

/\

l,

-,

VoI 3, No 3, JuIy - Septetnber 1994

(DBP)

of

95-115 mm

Hg

after

a

minimum of

2 weeks

with

no therapy were

entered

into

the study.

Patients

with

malignant

or

accelerated

hyperten-sion, and/or any other

severe

concomitant pathologic

condition

were

excluded

from

the

study.

The patients were informed

of

the nature

and

purpose

of

the study and were

asked

to

give

their

consent to

participate.

Study

design

A

2-week

placebo

run-in period was followed by

8

weeks

of

active treatment

with

5-10

mg

of amlodipine

in

a

single-blind

fashion.

Patients

visited the

clinic

at 2-week

intervals.

Standing and supine pulse rate and

BP

were measured in

triplicate

at each

visit.

Hematologic

and

biochemical

tests

were carried out

at the end

of

the placebo

run-in

phase, and

after

8 weeks

of

treatment

with

amlodipine.

A

12-lead

electrocardiogram

(ECG)

was obtained

on

entry to

the

study

and at the end

of

the

treatment

with

amlodipine.

At

the

end

of

the placebo

run-in

phase

and

the

treatment

with

amlodipine, ambulatory BP

was measured

for

24-h period using

an automated,

nonin-vasive device

(9O2O7

ABP

Monitor,

Space

Labs Inc,,

Houston,

TX, U.S,A.).

MEAN SUPINEBLOOD

PRESSURE

Placebo Amlodipine therapy

-

-

-

-:

Blood

Pressure

(mmHg)

Entry

Week

0

Week 2

*

= P < 0.05 comPared witb week 0

**

[image:2.595.51.548.421.737.2]

= P

(

0.005 comPared with week 0

Figure 2. Mean sphygmomanontetric blood pressure

Anlodipine on 24-Hour Atnbulatory Blood

Pressure

17l

A two-tailed

t

test was used to compare the mean

baseline

final

changes

in

clinic BP,

daytime

and

nightime 24-h ambulatory BP, heart rate,

and ECG

parameters.

Statistical significance

was calculated

at

5%

level.

RESULTS AND DISCUSSION

Patients

Twenty

patients (14

men,6

women)

with

a mean age

of47

years (range

of

29

to

64 years) were entered

into

the study.

Three patients

failed

to

fulfill

the

BP criteria

at the end

of

the placebo phase and were

withdrawn.

One

patient failed to finish the study,

because

he

had

to

move to

another

city

and

so

was excluded

from

the analysis.

Of

the

remaining

16

patients,

seven

patients

had

not

received any previous therapy, three patients

had

received diuretics

only, three patients had

received

beta-blocker, and three patients had received

ace-in-hibitor.

Those drugs were

withdrawn

before

the study. Eleven patients

required

an increase

in

dose

to

l0

mg

of

amlodipine once

daily

and

five

remained

on

5

mg daily.

MEAN STANDING BLOOD PRESSURE

Amlodipine therapy

\

.tt

l+

-\

t72

Susalit and Sidabutar

r20

100 Heatt rate

80 (beats/min)

Blood pressure (mmHg)

68107214161820222424

[image:3.595.57.552.57.404.2]

Time of day (h)

Figure 3. Mean blood pressure and heart rate over a 24-h period using anbulatory nonitoring

Sphygmomanometric

BP

Mean sphygmomanometric BP measurements

for

the

16 patients at each

visit are

shown

in Fig.

2. Significant decreases

in

BP were achieved

after 2 weeks (148196 mm Hg

supine,

146197 mmm Hg standing) and 8 weeks

(133/88

mm Hg supine, 133189

mm Hg

standing)

of

treatment

with

amlodipine

compared

with

values at the

end

of

the placebo

run-in

phase

(166/105 mm

Hg

supine,

1641106

mm

Hg

standing).

Table

1. Mean daytime

and nighttime 24-h ambulatory

blood pressure and heart rate.

A

60

200

180

Med

J

Univ Indon

Placebo

Amlodipine

24-h ambulatory BP

The

mean

hourly BP and

HR

over

24-h period

are

shown

in

Fig. 3. A

reduction

in

BP

was

observed

throughout the 24-h period after

treatment

with

am-lodipine

compared

with

placebo

without altering

the

circadian pattem.

No significant

changes

in

heart rate

was observed.

Comparison of mean daytime and mean

nighttime

BP values on amlodipine and on placebo are shown

in Table

1.

Both daytime

and

nighttime

BP was

significantly

reduced

after treatment

with

amlodipine,

with

no change

in

HR.

Side effects

One

patient on

l0

mg

dose

of amlodipine

developed ankle edema

which

disappeared after reducing the dose

up to 5 mg. There were no

significant

hematologic

or

biochemical

changes and no changes in the

electrocar-diograms.

CONCLUSIONS

The results

of

this study

clearly

show that once

daily

amlodipine provides

24-hBP control without

altering

160

140

r20

100

80

60

Placebo

Amlodipine

Daytime

Systolic BP (mm Hg)

*

Diastolic BP (mm Hg)

*

Heart rate (beats/min)

**

Nighttime

Systolic BP (mm Hg)

*

Diastolic BP (mm Hg)

*

Heart rate (beats/min)

**

l@

101 88

154

97 68

139

89 89

135

84 70

*pvalue<0.05

[image:3.595.58.291.584.761.2]

Vol 3, No 3, July - September 1994

the

physiologic

circadian

pattern

of

BP

variation.

Am-lodipine

was

well

tolerated

in

this study.

REFERENCES

1.

rùy'ebster

I,

_{Robb OI, Ieffers A, Scott AK,}

Petrie IC, Towler

HM.

Once

daily

amlodipine

in

the treatment

of

mild

to

moderate hypertension. Br

I

Clin Pharmacol 1987 ;27 :7

l3-9.

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Abemethy DR. Amlodipine: Pharmacokinetic profile

of

a low c)earance calcjutn antagoùst.

I

Cardjovasc Pharmaco)

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Amlodipine on 24-Hour Atnbulatory Blood

Pressure

173

Faullcrer ID, McGibney D, Chasseaud LF, Perry IL, Taylor

IW. The pharmacokinetics of amlodipine in healthy volun-teers after single intravenous and oral doses and after 14

repeated oral doses given once daily, Br

I

Clin Pharmacol 1986;22:21-5.

\ililliams _{DM, Cubeddu LX. Amlodipine pharmacokinetics}

in healthy volunteers. J Clin Pharmacol 1988;28:990-4. Frick MH, McGibney D, Tyler HM. Amlodipine : A double-blind evaluation

ofthe

dose-response relationship in mild to moderate hypertension.

I

Cardiovasc Pharmacol 1988;

l2(suppl 7) : 576-9.

Iulius S.

Amlodilne in

hypertension; an overview

of

the clinical dossier. J Cardiovasc Pharmacol 1988;12(suppl 7) :

s27-34.

4.